Submissions for variant NM_001042492.3(NF1):c.3496+5G>A

dbSNP: rs786202564

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686312	SCV000813825	uncertain significance	Neurofibromatosis, type 1	2024-05-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 26 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 566489). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.3496+5G>C nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18546366; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001766463	SCV002009010	likely pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate aberrant splicing leading to a predicted null allele in the majority of transcripts, with a minor amount of residual full-length transcript present (Morbidoni et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33673681)
Genome-Nilou Lab	RCV000686312	SCV002560302	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004559351	SCV005047731	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-16	criteria provided, single submitter	clinical testing	The c.3496+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 26 in the NF1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.